Method of producing a polymer network

ABSTRACT

In a process, a polymer is crosslinked and then reversibly bound to a template that is dissolved or suspended in a solvent. The polymer thereby acquires a conformation adapted to the template such that an interaction enthalpy between the template and the polymer is increased by more than 0.1 kcal/mole. The template can be a chemical compound or a biological structure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 09/856,983, filedSep. 17, 2001 now U.S. Pat. No. 7,291,686, which was the NationalizationStage of International Application No. PCT/EP99/09199, filed Nov. 26,1999, both applications hereby incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a process for the preparation of apolymeric network.

BACKGROUND

Polymeric structures which have pores in which a given substrate can beselectively bonded are of interest in a whole series of industrialapplications. In this connection, reference may be made to substanceseparation processes, catalytic processes or the use of these polymericstructures as sensors.

WO 93/09075 describes a process for the preparation of a polymericstructure, in which a polymer is prepared by free-radical polymerizationfrom the monomers in the presence of a crosslinking reagent andsimultaneously in the presence of a substrate. Imprinting polymers areproposed for use in chromatography, in catalysis, as biosensors or assynthetic antibodies. G. Wulff gives an overview in Angew. Chem., Int.Ed. Engl. 34 (1995) 1812-1832.

The imprinting technique, however, has a number of disadvantages. Thusthe imprints show an unacceptable peak broadening and, as a rule,incomplete substance elution in the chromatographic test, the latterleading to the cross-contamination of further product fractions.Industrial application of the imprints in chromatography is thusessentially excluded. Likewise, the imprints as a rule have a lowloading ability with substrate, essentially in the per thousand range,as a result of which, obviously, an only extremely small quantitativethroughput can be achieved and an industrial separation process couldonly be carried out uneconomically.

In J. Org. Chem. 63 (1998) 7578-7579, Menger et al. describe a processin which, starting from a combinatorial mixture, polyacrylic anhydrideis reacted with three or four amines selected more or less at random, 14different amine combinations in 96 different concentration ratiosleading to 1344 different polymers. The polymers were employed in thecatalytic dehydrogenation of a beta-hydroxyketone, where, however, lessthan 1 percent of all polymers were suitable for the catalytic processat all on account of the reaction rate. In connection with theexperiments, it was observed that the polymers gradually develop abetter catalytic activity in the presence of the substrate. However, thepolymeric structures with improved activity were not stabilized, butlabile structures were obtained such that the catalytically more activestructures were destroyed by changes in the pH or the temperature.

DESCRIPTION

In process for the preparation of a polymeric network:

-   -   (i) one or more polymers are made available which can be        crosslinked with one another intramolecularly or        intermolecularly or intra- and intermolecularly by covalent or        non-covalent bonding,    -   (ii) the conformation of at least one of the polymers is adapted        to at least one template compound with obtainment of at least        one preferred conformation of the at least one polymer and    -   (iii) at least one of the preferred conformations obtained        according to (ii) is fixed by crosslinkage.

The term “template compound”, as is used in the context of the presentapplication, includes all compounds on which at least one conformationof the at least one polymer employed is adaptable. Thus possiblecompounds are all those which lead to a preferred conformation of the atleast one polymer employed by interaction with the polymer. Theinteraction must in this case not take place with the polymer per se,but can also take place with a polymeric structure which is derived fromthe polymer employed, as is described further below.

Accordingly, template compounds which are possible are both chemicalcompounds and also biological structures, such as microorganisms, withrespect to which, inter alia, e.g. pathogenic organisms, preferablyviruses, bacteria or parasites may be mentioned. Likewise, for example,cells, fragments or constituents of cells, epitopes, antigenicdeterminants or receptors may be mentioned.

In the process according to the invention, the concentration of thetemplate compound employed in solution or suspension is basically freelyselectable. Preferably, the concentration is in the range from 0.25 to300 mmol/l, based on the solvent or solvent mixture employed. Thesolvents in which the template is employed are likewise essentiallyfreely selectable. Organic and aqueous solutions are preferred,preferred solvents being, inter alia, chlorohydrocarbons having up tothree C atoms, nitrites such as acetonitrile, esters such as ethylacetate, ketones such as methyl ethyl ketone or acetone, open-chain orcyclic ethers such as THF or dioxane or aromatic compounds such astoluene or xylenes or mixtures of two or more of these compounds. The pHrange of the solutions is essentially freely selectable and can becoordinated with the polymers and the template compound. Preferably, thepH range during fixing is in the range from 3 to 12, preferably in therange from 4 to 9 and particularly preferably in the range from 6 to 8.

The term “preferred conformation”, as is used in the context of thepresent invention, designates a conformation of the polymer whichresults from one or more steps of the process according to theinvention, the interaction enthalpy between the preferred conformationand the template compound being greater in amount than the interactionenthalpy between the template compound and that conformation which thepolymer has before this one or before this number of steps.

Preferably, this difference in amount in the interaction enthalpy isgreater than 0.1 kcal/mol, particularly preferably than 1 kcal/mol andvery particularly preferably greater than 3 kcal/mol.

As already indicated and described in detail further below, thepolymeric networks prepared according to the invention can be employed,inter alia, in substance separation processes. It is obviously possiblehere that substances which are to be separated under the reactionconditions which occur during the preparation of the polymeric networkare not stable or only inadequately stable or, for example, are notavailable. In this case, for example, compounds which are homologous toor structurally related to the substances to be separated, preferablyisosteric, can be employed as template compounds.

The adaptation of the conformation can be carried out here, inter alia,by interaction of the polymer with the template compound. It is alsopossible, for example, that two or more polymer strands of polymerswhich are identical to or different from one another are crosslinked andthe resulting polymeric structure interacts with the at least onetemplate compound and thus the conformation of the polymeric structureand thus also the conformation of the polymer employed is adapted to thetemplate compound.

It is furthermore possible that, by intramolecular crosslinkage of apolymer strand, a conformation is formed which interacts with the atleast one template compound, the conformation of the polymer beingadapted to the at least one template compound. Embodiments in which suchan intramolecular crosslinking takes place are possible in the contextof the present invention in the case of all suitable polymers. Polymersare particularly preferred which have a molar mass of more than 10,000g/mol, further preferably of more than 30,000 g/mol and particularlypreferably of more than 100,000 g/mol.

Furthermore, the present invention also includes embodiments in whichthe adaptation of the conformation is carried out such that, in theabsence of the at least one template compound, polymeric structures aresynthesized by inter- or intramolecular crosslinking whose conformationsare adapted to the at least one template compound by specific selectionof the at least one polymer and/or of the at least one crosslinkingreagent employed. In this case it is possible, for example, that thesteps (ii) and (iii), as mentioned above, can be carried out in onestep. In the case of crosslinkage in the absence of the at least onetemplate compound, however, it is also possible that polymericstructures are synthesized which are roughly adapted to the at least onetemplate compound, where a more accurate adaptation can be carried outby further crosslinking steps in the presence or absence of the at leastone template compound.

Accordingly, all polymers which can be crosslinked intra- and/orintermolecularly and which can interact per se or after crosslinkingwith the at least one template compound can be employed in the processaccording to the invention.

In the context of the present invention, the term “interaction” isunderstood as meaning all suitable covalent and non-covalentinteractions.

Possible interactions of the at least one polymer or one polymericstructure employed, which is synthesized, for example, by intra- orintermolecular crosslinking, as described above, with the at least onetemplate compound are, inter alia:

-   -   hydrogen bonds;    -   dipole-dipole interactions;    -   Van der Waals interactions;    -   hydrophobic interactions;    -   charge-transfer interactions, eg. π- π interaction;    -   ionic interactions;    -   coordinative bonding, e.g. to transition metals;    -   combinations of these interactions.

Obviously, covalent bonds between polymer and/or polymeric structure andthe at least one template compound are possible. If the polymer networkprepared in the process according to the invention is used in, forexample, substance separation processes, interactions between polymerand/or polymeric structure and the at least one template compound areparticularly preferred, by means of which the at least one templatecompound is reversibly bonded.

If the at least one polymer employed interacts per se with the at leastone template compound, according to the process according to theinvention it has at least one functional group by means of which thisinteraction can be formed. If the conformation of the polymer which isformed by interaction with the at least one template compound is fixedby crosslinkage, it is possible, inter alia, that the crosslinkage takesplace via the functional group via which the interaction with the atleast one template compound was formed. Preferably, the polymer has atleast one further functional group via which the crosslinkage takesplace.

The term “functional group”, as is used in the context of the presentinvention, accordingly includes all chemical structures via whichcovalent and/or non-covalent interactions can take place. In particular,hydrocarbon chains and further structural units via which Van der Waalsinteractions can be formed also come under the term of functional group.

A particularly suitable structure of the polymers employed isaccordingly present if the functional groups in the polymer which arecapable of interaction are able, according to type and/or number and/ordensity and/or distribution, to bond a specific template compound. Veryparticularly suitable polymers are those which are able to bond aspecific template compound bi-, tri-, oligo- and/or polyvalently in morethan one molecular position. Accordingly, two or more functional groupswhich are optionally spatially separated by at least one group which isinert to an interaction can be responsible for the interaction.

The term “in the polymer”, as is used in the context of the presentinvention, relates, inter alia, to polymers in which the at least onefunctional group which is used for the formation of the interaction withthe substrates and/or for the crosslinking is present in the polymerstrand. The term likewise relates to polymers in which the at least onefunctional group is present in at least one side chain of the polymerstrand, and also to polymers in which at least one type of a functionalgroup is present both in the polymer strand and in at least one sidechain of the polymer strand.

Accordingly, in the process according to the invention generally bothderivatized and non-derivatized polymers can be employed.

The at least one functional group which is needed in the polymer for theformation of the interaction with the at least one template compoundand/or for crosslinkage can accordingly already be present in theoriginal polymer and does not necessarily have to be introduced into thepolymer by subsequent derivatization. Inter alia, for example, the aminoor formyl groups in polyvinylamine or, for example, the hydroxyl oracetyl groups in polyvinyl alcohol may be mentioned by way of examplehere.

In the process according to the invention it is possible, inter alia, to“designate” the receptor-template interaction using made-to-measurereceptor groups by derivatization of at least one polymer which isemployed in the process in derivatized form. In the context of thepresent invention, the degree of derivatization can be influenced heresuch that the best possible interaction with the template is achieved.It is likewise possible to designate the adaptation of the conformationof the at least one polymer in the absence of the at least one templatecompound by specifically introducing certain crosslinking possibilitiesor interaction possibilities into the polymer, for example by means ofthe functional groups introduced by derivatization.

If one or more polymers are first derivatized in the process accordingto the invention and then employed in the process according to theinvention, the derivatization can take place according to all suitableprocesses, for example processes known from the prior art.

In order to equip polymers which have functional groups with receptorgroups and to derivatize them in this way, three routes can bementioned, inter alia, which are listed in M. Antonietti, S. Heinz,Nachr. Chem. Tech. Lab. 40 (1992) No. 3, pp. 308-314. According to thispublication, derivatized polymers are obtainable by means of randompolymerization or copolymerization, by means of the preparation of blockcopolymers and by means of the preparation of surface-functionalizedpolymer particles. These preparation routes start from derivatizedmonomers from which the polymer is obtained.

A further possibility of derivatizing polymers is the polymer-analogousreaction of polymers having functional groups with derivatizingcompounds.

Polymer derivatizations are carried out, for example, on solid surfacesby heterogeneous reaction. This group includes, inter alia, carrieractivation and carrier immobilization, in which a nucleophilic substanceis customarily heterogeneously bonded to a polymer, e.g. epoxypolyacrylic ester or BrCN-sepharose, as is described, for example, in P.Mohr, M. Holtzhauer, G. Kaiser, Immunosorption Techniques, Fundamentalsand Applications, Akademie Verlag, Berlin (1992), pp. 34-40.

In a preferred embodiment, in the process according to the invention (i)a derivatized polymer can be made available which is prepared byreacting a polymer having at least one functional group with at leastone activating reagent or a derivative of an activating reagent, wherethis reaction can take place homogeneously or heterogeneously,preferably homogeneously.

As a rule, the activating reagent is in this case selected such that theat least one functional group of the polymer reacts with the activatingreagent during the reaction and is thus improved in its reactivity in asubsequent reaction with a derivatizing agent.

Accordingly, the present invention also describes a process in which thereaction product from the polymer having at least one functional groupand the activating reagent is reacted with a derivatizing reagent.

In the context of this embodiment of the process according to theinvention, the polymer having at least one functional group can bereacted simultaneously, i.e. in the sense of a “one-pot reaction” withat least one activated and/or at least one non-activated derivatizingreagent and/or an activating reagent.

By means of this reaction of the activated polymer having at least onefunctional group with a derivatizing reagent, a desired radical can beintroduced into the polymer.

If a polymer was reacted here with different activating reagents, theseactivated functional groups can have different reactivity to one or morederivatizing reagents. Accordingly, it is possible in the context of theprocess according to the invention to derivative functional groupsselectively in this manner. The term “selective” in this connectionmeans that a polymer which has, for example, two or more functionalgroups which are different from one another is reacted with, forexample, two different activating reagents such that a subsequentreaction with a derivatizing reagent for derivatization takes placemainly to exclusively on the activated functional group(s) which is orare activated with one of these two activating reagents, as a rule onthe functional group(s) more reactively activated with respect to thederivatizing reagent.

In the process according to the invention, it is furthermore possible toreact the activating reagent before the reaction with the polymer havingat least one functional group in order then to react this reactionproduct with the polymer having at least one functional group.

The present invention therefore also describes a process, as describedabove, in which the derivative of the activating reagent is obtained byprior reaction of the activating reagent with a derivatizing reagent.

A further embodiment of the present invention consists in reacting thepolymer having at least one functional group with various produts fromreactions of activating reagents and derivatizing reagents. Thus, forexample, a mixture of compounds can be reacted with the polymer, themixture of reaction products comprising an activating reagent and two ormore different derivatizing reagents. A mixture is likewise possiblethat comprises reaction products of a derivatizing reagent and two ormore different activating reagents. Of course, it is also possible,should this be necessary, to employ a mixture which comprises reactionproducts of two or more different activating reagents and two or moredifferent derivatizing reagents. Obviously, it is also possible in thecontext of the present invention to react the different reactionproducts of activating reagent and derivatizing reagent not as amixture, but individually and in the desired sequence with the polymerhaving at least one functional group.

Accordingly, the present invention also describes a process as describedabove, in which the polymer having at least one functional group isreacted with at least two different derivatives of an activating reagentand the reactions are carried out successively with one derivative ineach case.

Activating reagents which can be employed in principle are allactivating reagents known from the literature. The article by P. Mohr,M. Holtzhauer, G. Kaiser already cited above, which in this respect isincluded completely by way of reference in the context of the presentpatent application, gives, for example, an overview on a whole series ofactivating reagents which can be employed for the activation of variousfunctional groups.

In particular, chloroformic acid esters and chloroformic acid estershaving electron-withdrawing radicals may be mentioned here.

In particular, the present invention describes a process in which theactivating reagent is derived from a compound of the following structure(I):

where R₁ and R₂ are identical or different and can be straight-chain,branched-chain or bridged to give a carbocycle or a heterocycle and areselected such that the activating reagent or the derivative of theactivating reagent can be reacted in homogeneous phase with the polymerhaving at least one functional group.

R₁ and R₂ here can be, for example, cycloalkyl, cycloalkenyl, alkyl,aryl or aralkyl radicals having up to 30 C atoms.

In a preferred embodiment, the present invention describes a process inwhich the activating reagent is derived from a compound of the followingstructure (I′)

where R₃ to R₁₀ can be identical or different and can be hydrogen,straight-chain or branched-chain alky, aryl, cycloalkyl, heterocyclicand aralkyl radicals having up to 30 C atoms, or else two or more of R₃to R₁₀ can in turn be bridged to give a carbocycle or heterocycle andare selected such that the activating reagent or the derivative of theactivating reagent can be reacted in homogeneous phase with the polymerhaving at least one functional group.The present invention further describes a process in which theactivating reagent has the following structure (II)

where R₃ to R₁₀ are as defined above.

In a likewise preferred embodiment, the present invention describes aprocess in which the activating reagent is derived from a compound ofthe structure (II), as indicated above, where R₃ to R₁₀ is in each casehydrogen.

The compounds having the structures (I), (I′) and (II) can be preparedby all customary processes known from the prior art. Such a process forONB-Cl is given, for example, in P. Henklein et al., Z. Chem. 9 (1986),p. 329 ff.

Using the activating reagents or the derivatives of activating reagentsas described above, all polymers which have at least one functionalgroup which is reactive with respect to the activating reagents can inprinciple be reacted.

Very generally, polymers which have as at least one functional group agroup which has at least one nucleophilic unit are employed in theprocess according to the invention.

Preferred functional groups of the polymer having at least onefunctional group which may be mentioned are, inter alia, OH groups,optionally substituted amine groups, SH groups, OSO₃H groups, SO₃Hgroups, OPO₃H₂ groups, OPO₃HR₁₁ groups, PO₃H₂ groups, PO₃HR₁₁ groups,COOH groups and mixtures of two or more thereof, where R₁₁ in each caseis selected such that the activating reagent or the derivative of theactivating reagent can be reacted with the polymer having at least onefunctional group in homogeneous and/or heterogeneous phase. Likewise,the polymers having at least one functional group can also containfurther polar groups, for example —CN.

Both natural and synthetic polymers can be employed as the polymerhaving at least one functional group. Possible restrictions in theselection of the polymers only result in that the reaction of thepolymer is performed in homogeneous phase in the context of the processaccording to the invention and from the later intended use of thederivatized polymer.

In the context of this invention, the term “polymer” here obviouslylikewise includes higher molecular weight compounds which are designatedin polymer chemistry as “oligomers”.

Without wishing to be restricted to certain polymers, the following maybe mentioned, inter alia, as possible polymers having at least onefunctional group:

-   -   polysaccharides, e.g. cellulose, amylose and dextrans;    -   oligosaccharides, e.g. cyclodextrins;    -   chitosan;    -   polyvinyl alcohol, poly-Thr, poly-Ser;    -   polyethyleneimine, polyallylamine, polyvinylamine,        polyvinylimidazole, polyaniline, polypyrrole, poly-Lys;    -   poly(meth)acrylic acid (esters), polyitaconic acid, poly-Asp;    -   poly-Cys.

Likewise, in principle not only homopolymers, but also copolymers and inparticular block copolymers and random copolymers, are suitable to beemployed in the present process. Here, both copolymers havingnon-functionalized components such as, for example, co-styrene orco-ethylene or alternatively copolymers such as, for example,co-pyrrolidone may be mentioned.

If the polymers in the process according to the invention arederivatized in homogeneous liquid phase, then, in order to achieveoptimum solubility, preferably mixed-functional or alternativelyprederivatized polymers are employed. Examples of these which may bementioned are, for example:

-   -   partially or completely alkylated or acylated cellulose;    -   polyvinyl acetate/polyvinyl alcohol;    -   polyvinyl ether/polyvinyl alcohol;    -   N-butylpolyvinylamine/polyvinylamine.

Likewise, polymer/copolymer mixtures can also be used. All suitablepolymer/copolymer mixtures can be employed here, for example mixtures ofthe polymers and copolymers already mentioned above, where, inter alia,the following, for example, are to be mentioned here:

-   -   poly(acrylic acid)/co-vinyl acetate;    -   polyvinyl alcohol/co-ethylene;    -   polyoxymethylene/co-ethylene;    -   modified polystyrenes, e.g. copolymers of styrene with        (meth)acrylic acid (esters);    -   polyvinylpyrrolidone and its copolymers with        poly(meth)acrylates.

All of these abovementioned polymers, which are accessible toderivatization, can obviously also be employed in underivatized form inthe process according to the invention.

If, as described above, the polymer having at least one functional groupis reacted with an activating reagent such as a compound of thestructure (II), then, as likewise described above, this reaction productcan be reacted with a derivatizing reagent.

Here, in principle, all reagents which can react with the activatedpolymer and lead directly or indirectly to the desired derivatizedpolymer can be used. Inter alia, compounds which have at least onenucleophilic group are employed in the process according to theinvention as derivatizing reagents.

For example, derivatizing reagents are used which have the generalcomposition HY—R₁₂. Here, Y is, for example, O, NH, NR₁₃ or S, where R₁₂and R₁₃ can generally be freely selected. For example, they are an alkylor aryl radical which is optionally suitably substituted.

In addition, it is also possible to react the activated polymer withnucleophilic chiral compounds. Examples of such chiral nucleophileswhich may be mentioned are, for example: borneol, (−)-menthol,(−)-ephedrine, α-phenylethylamine, adrenaline, dopamine.

A further possibility is to react the activated polymer with a mono- orpolyhydric alcohol or thiol containing an amino group in the processaccording to the invention. If the polymer comprising at least onefunctional group is activated, for example, with ONB-Cl, the mono- orpolyhydric alcohol containing the amino group or the mono- or polyhydricthiol containing the amino group reacts selectively with the aminogroup. The OH or SH groups thus introduced into the polymer can then beactivated again in a further step with, for example, one of theactivating reagents described above, whereby chain extensions andbranchings are facilitated, depending on the functionality of thealcohols or thiols originally employed.

In another embodiment of the process according to the invention alreadydescribed above, the polymer having at least one functional group isreacted with an activated derivatizing reagent, the latter beingobtained from the reaction of an activating reagent with thederivatizing reagent.

In the process according to the invention, activated derivatives ofamines, alcohols, thiols, carboxylic acids, sulphonic acids, sulphates,phosphates or phosphonic acids are preferably reacted with the polymerhaving at least one functional group, where, in turn in a preferredembodiment, the compounds are activated with ONB-Cl.

Inter alia, these activated derivatizing reagents which can be reactedwith the polymer having at least one functional group thus have thefollowing general structures (III) to (IX):

where R₃ to R₁₀ are as defined above and R₁₄ to R₂₀ are in generalsubject to no restrictions, for example can also have chirality, and inthe process according to the invention are selected such that thereaction with the polymer having at least one functional group can becarried out in homogeneous phase. Here, the substituents R₁₄ to R₂₀ as arule are selected depending on the desired interaction with thesubstrate. Here, R₁₄ to R₂₀ can be identical or different and areradicals containing hydrogen, a straight-chain or branched-chain alkyl,aryl or aralkyl radical having up to 30 C atoms or correspondingheteroatoms.

Likewise, polyhydric amines, alcohols, thiols, carboxylic acids,sulphonic acids, sulphates, phosphates or phosphonic acids can bereacted with an activating reagent and this reaction product can bereacted with the polymer having at least one functional group, wherehere, in particular, polyols may be mentioned.

Obviously it is also possible to activate derivatizing reagents whichhave two or more different types of the abovementioned functional groupsand to react them with the polymer having at least one functional group.Examples which may be mentioned here, inter alia, are, for example,aminoalcohols.

In the context of the present invention, such polyhydric derivatizingreagents can selectively be partially or completely activated using anactivating reagent and reacted with the polymer having at least onefunctional group.

The reaction of the polymer having at least one functional group with anactivated, polyhydric derivatizing reagent can also be used in theprocess according to the invention for polymer crosslinking and furtherfor polymer stabilization and/or for polymer branching, in addition tothe fact that a suitable polymer according to (i) is made available.

Both the reaction of the polymer having at least one functional groupwith an activated derivatizing reagent and the reaction of the polymerhaving at least one functional group with an activating reagent andsubsequent reaction of the product with a derivatizing reagent by theprocess according to the invention make it possible to prepare polymerderivatives which have very different spatial arrangements andaccordingly can be used for a large number of applications in which thisspatial arrangement is of crucial importance.

Thus it is possible, for example, to realise arrangements which areconstructed as hairy rods, comb polymers, nets, baskets, dishes, tubes,funnels or cages.

In a likewise preferred embodiment, the present invention describes aderivative of the type under discussion here, which has at least onereceptor group which has a bonding unit decisive for the bonding of abiological or synthetic chemical substrate.

A made-to-measure derivative of this type for biological substrates thenhas corresponding receptor groups which have, for example, structuresalso occurring in nature or parts of structures of this type responsiblefor bonding, which can then interact with a biological substrate. Herein particular, for example, enzyme, amino acid, peptide, sugar, aminosugar, sugar acid and oligosaccharide groups or derivatives thereof maybe mentioned. It is essential for the above receptor groups that theprinciple of bonding of a receptor with a substrate occurring in natureis exclusively retained here, such that, for example, synthetic enzymes,binding domains of antibodies or other physiological epitopes can beobtained by means of this embodiment. Inter alia, in the context of thepresent invention a derivative of a polymer having at least threefunctional groups is selected here, as described above, in which atleast one receptor group is an amino acid residue or an amino acidderivative residue. Possible amino acids are, for example:

-   -   amino acids having aliphatic residues such as glycine, alanine,        valine, leucine, isoleucine;    -   amino acids having an aliphatic side chain which includes one or        more hydroxyl groups, such as serine, threonine;    -   amino acids which have an aromatic side chain, such as        phenylalanine, tyrosine, tryptophan;    -   amino acids which include basic side chains, such as lysine,        arginine, histidine;    -   amino acids which have acidic side chains, such as aspartic        acid, glutamic acid;    -   amino acids which have amide side chains, such as asparagine,        glutamine;    -   amino acids which have sulphur-containing side chains, such as        cysteine, methionine;    -   modified amino acids, such as hydroxyproline,        γ-carboxylglutamate, ο-phosphoserine;    -   derivatives of the amino acids mentioned or optionally of        further amino acids, for example amino acids esterified on the        carboxyl group or optionally the carboxyl groups with, for        example, alkyl or aryl radicals which can be optionally suitably        substituted.

Instead of the amino acid, the use of one or more di- or oligopeptidesis also possible, where in particular homopeptides, which are onlysynthesized from identical amino acids, may be mentioned. An example ofa dipeptide which may be mentioned is, for example, hippuric acid.Furthermore, beta-, gamma- or other structurally isomeric amino acidsand peptides derived therefrom such as depsipeptides can also be used.

Very generally, the activating reagents employed in the processaccording to the invention can be compounds of the general structure (X)

which are characterized in that R₀ is a halogen atom or a radical (X′)

and R₁′, R₂″ R₁″ and R₂″ are identical or different and are hydrogen,straight-chain or branched-chain alkyl, aryl, cycloalkyl, heterocyclicor aralkyl radicals having up to 30 C atoms or either R₁′ and R₂′ or R₁″and R₂″ or both R₁′ and R₂′ and R₁″ and R₂″ are linked to at least onecarbocycle or to at least one heterocycle or to at least one carbocycleand to give at least one heterocycle. In particular, compounds may bementioned by way of example here which have the following structures(X₁) to (X₃₉):

where R′″ is hydrogen or a straight-chain or branched-chain, optionallysubstituted alkyl, aryl or aralkyl radical having up to 30 C atoms.

In the context of the present invention, the crosslinkage according to(iii) can be achieved, for example, in that two or more strands ofderivatized or underivatized polymer are reacted directly with oneanother. This can be achieved, for example, in that the groupsintroduced by derivatization are constituted such that covalent and/ornon-covalent bonds can be connected between these groups. Verygenerally, it is possible that these covalent and/or non-covalent bondsare formed between groups which are attached to one polymer strand,and/or are formed between groups which are attached to two or morepolymer strands, such that two or more polymer strands can be connectedto one another via one or more sites by crosslinkage.

Obviously, the bonding of the at least one polymer to the carriermaterial can also take place via functional groups which are present inthe polymer itself or have been introduced into the polymer by suitablederivatization, as described above.

Likewise, it is also possible to employ for crosslinkage one or moresuitable crosslinking reagents with which, as described above, groupswithin a polymer strand and/or groups which are attached to a number ofstrands of optionally different, optionally derivatized polymers can becrosslinked in a covalent and/or non-covalent manner.

Inter alia, it is possible here, even in the selection of the at leastone polymer, to design its composition for later crosslinkage.Furthermore, it is in particular possible in the context of the presentinvention to design the derivatizing reagent with respect to itschemical composition, inter alia, with regard to later crosslinkage evenduring derivatization. In particular, the derivatizing reagent cancontain groups which are selective for covalent and/or non-covalentcrosslinkage.

Possible crosslinking reagents in principle are all suitable compoundsknown from the prior art. Accordingly, the crosslinkage can be carriedout, for example, in a covalently reversible manner, in a covalentlyirreversible manner or in a non-covalent manner, where in the case ofcrosslinkage in a non-covalent manner, for example, crosslinkages viaionic interaction or via charge-transfer interaction may be mentioned.Crosslinking processes or reagents of this type are described, interalia, in Han, K. K., et al., Int. J. Biochem., 16, 129 (1984), Ji, T.H., et al., Meth. Enzymol., 91, 580 (1983) and Means, G. and Feeney, R.E. Bioconj. Chem., 1,2 (1990).

With respect to non-covalent crosslinkage, an example which may bementioned is, for example, crosslinkage by shifting the pH, when atleast one basic and at least one acidic group are crosslinked with oneanother. Likewise, for example, non-covalent crosslinkage can take placewhen, in the case where two basic groups of, for example, polyallylamineare crosslinked with one another, a dibasic acid such as glutaric acidis added, or in the case where two acidic groups of, for example,polyacrylic acid are to be crosslinked with one another, a bifunctionalsuch as ethylenediamine is added. Likewise, a non-covalent crosslinkagecan be formed by way of example by complex-forming metal ions or bymetal complexes with free coordination sites. Non-covalent crosslinkageis preferably reversible and can therefore be employed in a preferreduse of the polymeric networks prepared according to the invention forrapid systematic interaction studies. Very generally, with respect tonon-covalent crosslinkage, reference can be made to all possibleinteractions which have already been presented above with respect to theinteraction between template and polymeric structure.

With respect to covalently reversible attachment, inter alia, bondingvia disulphide bridges or via labile esters or imines such as Schiff'sbases or enamines may be mentioned by way of example.

The chain length of the crosslinking reagents is in general arbitraryand can be adapted to the requirements of the particular process.Preferably, the chain length in the case of crosslinking reagents whichhave a carbon chain is in the range from 2 to 24 C atoms, preferably inthe range from 2 to 12 C atoms and particularly preferably in the rangefrom 2 to 8 C atoms.

Crosslinking reagents which may be mentioned which can lead tocovalently irreversible crosslinkage are, inter alia, bi- orpolyfunctional compounds such as diols, diamines or dicarboxylic acids.Here, for example, bifunctional crosslinkers are reacted with theactivated polymer derivative or the at least bifunctional activatedcrosslinking reagent is reacted with the non-activated polymerderivative. A covalently reversible crosslinkage can be realized, forexample, by connecting a sulphur-sulphur bond to a disulphide bridgebetween two groups attached to one or two polymer strands or byformation of a Schiff's base. Crosslinking via ionic interaction cantake place, for example, via two radicals, of which one, as a structuralunit, has a quaternary ammonium ion and the other has, as a structuralunit, for example—COO⁻ or —SO₃ ⁻A crosslinkage via hydrogen bridges can be formed, for example, betweentwo complementary base pairs, for example via the following structure:

Very generally, polymers to be crosslinked non-covalently can besynthesized in a complementary manner with respect to the crosslinkingsites, structural units complementary to one another being, for example,acid/triamine or uracil/melamine. Likewise, in the case of non-covalentcrosslinkage the crosslinking reagent can be complementary to thecrosslinking sites on the polymer strand. An example of this which maybe mentioned would be, for example, an amine group on the polymer strandand a dicarboxylic acid as a crosslinking reagent.

It is necessary in the context of the process according to theinvention, with respect to a crosslinking step, to activate at least oneof the functional groups which are involved in the crosslinkage, thusthis is essentially possible according to all processes which are knownfrom the prior art. In particular, the activation of a functional groupcan be carried out according to a process as is described in detailabove in the activation and derivatization of polymers.

If, in the process according to the invention, the crosslinkage takesplace via the use of at least one crosslinking reagent, thiscrosslinking reagent can in particular be a condensation compound whichis prepared by reaction of at least one functional group of a first lowmolecular weight compound having at least two functional groups with atleast one functional group of at least one further second low molecularweight compound having at least two functional groups, which can beidentical to the first or different from the first low molecular weightcompound, with obtainment of a condensation compound, the process beingcharacterized in that at least one of the functional groups involved inthis reaction has been activated before the reaction by reaction with acompound of the structure (X)

as defined above.

(Activated) crosslinking reagents which may be mentioned are, by way ofexample, compounds of the following structures (XI₁) to (XI₁₇) mentionedbelow;

An example of a crosslinking reagent to be used according to theinvention which may be mentioned below is a dimeric crosslinker which isprepared from phenylalanine and leucine by the process described above:

Example for the synthesis of a condensation compound to be used as acrosslinking reagent by the process according to the invention which maybe mentioned are the following reaction routes (A) and (B), in which theradical BNO represents the following structural unit (XII):

Reaction Route (A):

Reaction Route (B):

By means of this process, in which activated or non-activatedcrosslinking reagents can be prepared, it is of course also possiblespecifically to prepare polymers which can be employed in the processaccording to the invention and whose conformation can be adapted to atleast one template compound. It is possible here that by means of thisprocess, in which a condensation compound is synthesized, a polymer isprepared which is derivatized by the process already described above.Likewise, it is also possible to prepare an already derivatized polymer.

Very generally, in the case of covalent crosslinkage, inter alia, ester,amide, carbonate, hydrazide, urethane or urea compounds orthio-analogous or nitrogen-homologous bonds can be formed.

In a preferred embodiment of the process according to the invention, theconformation of at least one of the polymers is adapted in the presenceof at least one of the template compounds according to (ii).

Accordingly, the present invention relates to a process such asdescribed above, characterized in that the adaptation according to (ii)is carried out in the presence of at least one of the templatecompounds.

Inter alia, it is possible here to dissolve or to suspend the at leastone polymer in one or more suitable solvents and to mix it together withthe at least one template compound.

Inter alia, at the same time it is possible to add the at least onepolymer to a solution in which the at least one template compound ispresent dissolved in at least one solvent, where the template compoundcan also be present in suspended form. Microparticles, for example, maybe mentioned as a template compound which can be present in suspendedform.

Inter alia, it is further possible to add at least one template compoundto a solution in which the at least one polymer is present in dissolvedor suspended form in at least one solvent.

Obviously, two or more solutions can also be mixed together, where in atleast one solution the at least one polymer is present in dissolved orsuspended form and in at least one further solution the at least onetemplate compound is present in dissolved or suspended form.

If two or more polymers which are different from one another and/or twoor more different template compounds are employed, each polymer and/oreach template compound can be dissolved or suspended separately in oneor more suitable solvents and the individual solutions and/orsuspensions can be mixed together.

In this connection, embodiments are also possible in which a solution isemployed which contains two or more solvents, in which the at least onepolymer and/or the at least one template compound are both present indissolved or in suspended form.

Obviously, it is also possible to start from a template compound whichis already present bonded to at least one polymer, for example in theform of a complex or covalently, preferably covalently reversiblybonded. At the same time, the polymer to which the template compound isbonded can be a polymer whose conformation is adapted to this or anothertemplate compound in the further process. It is likewise possible tointroduce the template compound into the process via this polymer, butthe conformation of the polymer is not adapted in the further process tothis or another template compound, the polymer remaining in thepolymeric network or being removed from the polymeric network by asuitable process.

In one embodiment of the process according to the invention, at leastone conformation of the at least one polymer which is formed in thesolution or in the suspension or in solution and suspension in thepresence of the at least one template compound is fixed by crosslinkage.All suitable methods are possible as regards the crosslinkage.

In one embodiment of the process according to the invention, one or morecrosslinking reagents are added to the solution or the suspension or thesolution and suspension.

In a further embodiment of the process according to the invention, thecrosslinkage is carried out such that one or more covalent ornon-covalent or covalent and non-covalent bonds are formed between atleast one functional group of at least one polymer and one or morefunctional groups of at least one further polymer. In this case, thereaction conditions are preferably to be selected such that firstly theconformation of at least one of the polymers is adapted to at least oneof the template compounds and the preferred conformation obtained isfixed by crosslinkage by specific choice of the reaction conditions.

The functional groups of the respective polymers between which the bondsare formed can in this case themselves be present in the respectivepolymer strand. Likewise, it is also possible that at least one of thefunctional groups involved is a constituent of one or more side chainsof the respective polymer. Likewise, at least one side chain of at leastone of the polymers involved can also have two or more functional groupswhich are capable of the formation of the covalent or non-covalentbonds.

Obviously, process embodiments are also possible in which two or morefunctional groups of the polymers involved, which can be identical to ordifferent from one another, react directly with one another intra- orintermolecularly with formation of at least one covalent or non-covalentbond and two or more functional groups of the polymers involved, whichcan likewise be identical to or different from one another, are intra-or intermolecularly crosslinked via at least one crosslinking reagent.

Obviously, the present invention also comprises embodiments in which,for example, at least two similar or different crosslinking reagents arefirst reacted with one another with the formation of at least onecovalent and/or non-covalent bond and with obtainment of a newcrosslinking reagent. The new crosslinking reagent formed can theneither be reacted with firstly at least one functional group of at leastone polymer and then with at least one further functional group of atleast one further polymer. Likewise, these reactions of the newcrosslinking reagent can also proceed simultaneously. Obviously, thepresent invention also includes embodiments in which the adaptationaccording to (ii) takes place via the fixing according to (iii), suchthat in this case (ii) and (iii) are to be seen as at least one jointstep.

The crosslinkage via the reactions between two or more functional groupswith or without crosslinking reagent can obviously take place bothintra- and intermolecularly. Accordingly, the present invention alsoincludes embodiments in which exclusively intramolecular or exclusivelyintermolecular crosslinkages take place. The present invention furtheralso includes processes in which crosslinking is carried out both intra-and intermolecularly, where in the case in which two or more differentpolymers are employed, the intermolecular crosslinkages take placeexclusively between similar polymers or exclusively between differentpolymers or between both similar and different polymers.

In a likewise preferred embodiment of the process according to theinvention, the adaptation of the conformation of the at least onepolymer and the attachment of the at least one preferred conformationobtained take place together.

This is realizable, for example, in that the at least one crosslinkingreagent is brought into contact with the at least one polymer togetherwith the at least one template compound.

If the crosslinkage is carried out without crosslinking reagents, it is,for example, possible to select the reaction conditions such that theadaptation of the conformation of at least one of the polymers and thecrosslinkage take place together.

Very generally, it is possible for at least one of the crosslinkingreagents employed to have at least one functional group which is notused for the formation of the covalent or non-covalent bonds which leadto the crosslinkage of the polymers. With respect to this at least onefunctional group, it is furthermore possible for this to interact withat least one of the template compounds. Thus the process according tothe invention accordingly also includes embodiments in which, inaddition to at least one polymer, at least one crosslinking reagent alsointeracts with at least one template compound. Accordingly, it is alsopossible in the context of the present invention to adapt theconformation of at least one of the polymers to the at least onetemplate compound by interacting both the polymer and the crosslinkingreagent, which the polymer crosslinks intermolecularly, with a furtherpolymer or which the polymer intramolecularly crosslinks with the atleast one template compound.

The preferred conformation obtained according to (ii) and fixedaccording to (iii) can thus also be influenced by the crosslinkingreagent, where, inter alia, embodiments are also possible according towhich a preferred conformation is synthesized such that crosslinkingreagent, polymer and template compound interact with one another beforeattachment.

In a preferred embodiment of the process according to the invention, aprocedure is used here in which crosslinking reagent, polymer andtemplate compound are first mixed together at low temperature,preferably in the range from 0 to −70° C., such that the interactionsare developed, but the attachment by crosslinkage is largely suppressed.In a further step, the temperature is then increased in such a way thatattachment takes place.

In the context of the process according to the invention, it is moreoveralso possible that the preferred conformation according to (ii) onlyresults from interaction of at least one of the crosslinking reagentswith the at least one template compound. It is accordingly possible,inter alia, that at least one crosslinking reagent first reacts with atleast one polymer with formation of at least one covalent ornon-covalent bond, and simultaneously or thereafter interacts with atleast one of the template compounds, whereby a preferred conformation ofthe reaction product of crosslinking reagent and polymer is formed, andthis preferred conformation is attached by reaction of the reactionproduct of crosslinking reagent and polymer with a further polymer or byintramolecular crosslinkage.

The present invention therefore also describes a process, as describedabove, which is characterized in that the preferred conformationaccording to (ii) is influenced by interaction of at least onecrosslinking reagent with at least one template compound.

Of course, it is also possible for the preferred conformation to resultfrom the fact that, by means of the reaction of two or more functionalgroups which can be constituents of one or more side groups of one ormore polymers, a structure results which interacts with at least onetemplate compound in such a way that a preferred conformation resultswhich is attached by crosslinkage with at least one crosslinking reagentor by reaction of at least two functional groups of the at least onepolymer which contains the preferred conformation.

In a further preferred embodiment, in the context of the processaccording to the invention the adaptation of the conformation accordingto (ii) takes place in two or more steps.

Accordingly, the present invention also relates to a process, asdescribed above, characterized in that the adaptation of theconformation of the at least one polymer takes place in at least twosteps.

Inter alia, it is possible, for example, in this respect to bring atleast one polymer into contact with at least one template compound in afirst step according to a process, as described in detail above, andthereby to deform the conformation of the at least one polymer. In asecond step, for example, at least one further template compound, whichis different, for example, from the at least one template compound addedin the first step, can then be added. It is thereby also possible toadapt the conformation of the at least one polymer to the at leastsecond template compound. Likewise, it is possible that at least twopolymers which are different from one another are employed and, byaddition of the at least one template compound in a first step, theconformation of a polymer is adapted to the at least one first templatecompound, and by addition of at least one further template compound in asecond step the configuration of the other polymer is adapted to the atleast one further template compound.

It is likewise possible to employ more than two polymers which aredifferent from one another and, in one step in each case, to adapt theconformation of a polymer to the at least one template compound added inone step in each case.

Inter alia, it is possible in this connection to employ a number ofpolymers which are different from one another and by specific choice ofthe reaction conditions to adapt the conformation of a first polymer toa template compound in one step and to adapt the conformation of apolymer which is different from the first to the same template compoundin a further step under modified reaction conditions. Here, the templatecompound can in each case be added both in the first step and in thesecond step. However, it is also possible to add sufficient templatecompound as early as in the first step such that template compound nolonger has to be added in one of the following steps for the adaptationof the polymer conformation. Obviously, the present invention alsoincludes an embodiment of the process in which in one step, by means ofthe deformation, the reaction conditions change by themselves in such away that the adaptation of the conformation of the identical or of afurther polymer to the template compound takes place without influenceon the reaction conditions from outside. Inter alia, what is in mindhere is, for example, a temperature change and/or change of theviscosity in the system. It is likewise possible that by means of theadaptation of the conformation, the state of aggregation of one of thereactants changes in one step. Thus it is possible that by means ofaddition of template and change in the conformation, a polymer which waspresent in dissolved form changes into the suspended state as a solid.Likewise, a suspended polymer can go into solution.

In a preferred embodiment of the process according to the invention, inat least one step the conformation of the at least one polymer whichresults from the adaptation is fixed by crosslinkage. The presentinvention therefore also describes a process, as described above,characterized in that the adaptation of the conformation according to(ii) takes place in at least two steps and the conformation is fixed atleast once by crosslinkage.

Inter alia, it is possible here that the conformation of at least onepolymer, as described above, is adapted in one step and this at leastone conformation is fixed by crosslinkage, as described above. In afurther step, at least one conformation of the same or of anotherpolymer is adapted to at least one template compound, where this atleast one template compound can be identical to or different from thatemployed in the first step. The preferred conformation which is obtainedin this further step can be fixed either by crosslinkage oralternatively not be fixed.

In a preferred embodiment of the process according to the invention, atleast the preferred conformation which results from the last adaptationstep is fixed by crosslinkage. In a further preferred embodiment,functional groups which may be present, which lie, for example, on theoutside of the polymer network, are reacted with at least oneend-capping reagent. As an end-capping group, in principle any group canbe selected which makes a functional group inert or to the greatestextent inert to certain interactions. The end-capping group which can beused here is any suitable group according to the prior art. Depending onthe substrate, it is, for example, possible that the end-capping groupselected is a group which is not an H donor. Preferably,

is employed here, particularly preferably

Sterically demanding end-capping groups such as a t-butyl radical or anoptionally suitably substituted benzyl radical are further preferred.

By means of the end-capping process or by means of other suitablesubsequent reaction, it is very generally possible to introduceadditional, as a rule non-specific, interaction sites into the polymernetwork.

A process is likewise preferred in which, in the case where theadaptation is carried out in two or more steps, after each step thepreferred conformation obtained from this step is fixed by crosslinkage.

The present invention therefore also relates to a process, as describedabove, characterized in that, after each step the preferred conformationobtained from this step is fixed by crosslinkage.

With respect to the procedure, reference can be made to the adaptationand crosslinkage, as described above. In particular, it is possible tocarry out the adaptation and crosslinkage successively or simultaneouslyin one step, as is likewise described above.

Obviously, in the context of the process according to the invention itis also possible that at least one of the template compounds is notpresent in one or alternatively a number of steps in which theconformation of at least one polymer is adapted to at least one templatecompound.

The present invention therefore also relates to a process, as describedabove, characterized in that at least one step is carried out in theabsence of the at least one template compound.

Thus it is possible, inter alia, that by intramolecular crosslinkage ofa polymer or two or more different polymers or by intermolecularcrosslinkage of a polymer or two or more different polymers theconformation can be influenced such that the preferred conformationresulting from crosslinkage is adapted to one or more templatecompounds. In particular, it is possible here that the chemicalstructure of the polymers and/or the specific nature of the at least onecrosslinking reagent are selected such that the at least one preferredconformation, which results from the crosslinkage, is adapted to atleast one template compound.

It is further also possible in this respect that the conformation isadapted without crosslinkage in the absence of the at least one templatecompound in one or more steps. Inter alia, it is possible here that theconformation is influenced in a first step by addition of at least onecrosslinking compound without crosslinking taking place, where here toothe cases are included in which, for example, although a crosslinkingreagent reacts with one or more polymers, the preferred conformation isstill not fixed.

In a preferred embodiment, the process according to the invention iscarried out in such a way that the at least one preferred conformationwhich is obtained from each step is fixed by crosslinkage irrespectivelyof whether the adaptation takes place in the presence or absence of theat least one template compound.

With respect to the embodiment in which the at least one templatecompound is not present in one or more steps in which an adaptationtakes place, it is possible, inter alia, to adapt the at least oneconformation of the at least one polymer stepwise to the at least onetemplate compound. In a first step, for example, a conformation can befixed here which is only roughly adapted to the at least one templatecompound. In a further step, the conformation fixed in the first stepcan again be influenced and the conformation obtained, which is nowbetter adapted to the at least one template compound than theconformation fixed in the first step, can be fixed. This process can becontinued until the conformation corresponds to the desired preferredconformation.

All suitable processes can be employed for this stepwise adaptation ofthe conformation.

As an example of a stepwise adaptation, inter alia, the possibility maybe mentioned of employing, in a certain step, one or more crosslinkerswhose chain length is shorter than that of the crosslinkers of thepreceding step. In this manner, it is possible, for example, for aconformation resulting from crosslinkage, in the form of a two- orthree-dimensional pore, to be made narrower stepwise. Obviously, thepresent invention also includes embodiments of the process in which inany two or more steps the same crosslinkers are employed, thesecrosslinkers crosslinking, for example, different polymers in each casein different steps, causing different intramolecular crosslinkages atvarious sites in a polymer or causing an intramolecular crosslinkage inone step, and an intermolecular crosslinkage in another step.

Obviously, it is also possible to change the chemical structure of thecrosslinker instead of the chain length or additionally to the chainlength, such that in various steps various polymers in each case can becrosslinked and/or polymers can in each case be crosslinked with oneanother intra- and/or intermolecularly in various sites. The presentinvention further also includes embodiments in which crosslinking iscarried out in a first step and a crosslinkage takes place in anyfurther step, which is realized by reacting the at least onecrosslinking reagent, through which crosslinkage takes place in thefurther step, in the crosslinkage, for example, with at least onefunctional group which results due to the crosslinkage in the first stepor is incorporated into the polymeric structure which was obtained fromthe first crosslinking step by at least one of the crosslinking reagentswhich are employed in the first step.

Very generally, in a stepwise adaptation the nature of the at least onecrosslinking reagent and the concentration of at least one of thecrosslinking reagents can be varied in each step. Likewise, it is alsopossible, instead of this and/or additionally, to vary the reactionconditions such as nature of the solvent, pressure, temperature, pH ofthe solution and/or the suspension in which the crosslinkage takes placeor one or more further suitable parameters.

If the adaptation and/or the attachment takes place in a number ofsteps, the degree of crosslinkage which takes place per crosslinkingstep is essentially arbitrary. In a preferred embodiment, the degree ofcrosslinking per step is in the range from 2 to 5%, a total degree ofcrosslinking of preferably 8 to 30% being achieved. The percentages withrespect to one step are here in each case based on the number of monomerunits of a polymer chain which is only cross-linked with one furtherpolymer chain. The percentage with respect to the total degree ofcrosslinkage is based on the total of all monomer units in the polymernetwork. For the degree of crosslinking of a polymer chain which iscrosslinked with two further polymer chains, values of the degree ofcrosslinkage per step in the range from 4 to 10% accordingly result.

Owing to the crosslinkage, in the context of the process according tothe invention a polymer network is constructed which has two- orthree-dimensional cells via which the polymeric structure interacts withthe at least one template compound. Particularly preferably, the degreeof crosslinking and/or the crosslinking reagent is selected such that nomultiple-layer solvate shells are formed in these interacting cells ofthe polymer structure. Preferably, this property of the interactingcells can be influenced by the chemical nature of the polymers and/orcrosslinking reagents used, in that, for example, hydrophilic groupsmake solvent access to the interacting cell difficult when using polarsolvents.

As far as the specific selection of the at least one polymer employed,the nature of the at least one crosslinking reagent, the variation ofthe chain length and/or the chemical structure of the cross-linkingreagents, the degrees of crosslinking achieved and all further reactionparameters, such as described above by way of example, are concerned,predictions or estimates can be made in the process according to theinvention, for example, by computer-modelling procedures.

Obviously, it is also possible that the reaction conditions which arenecessary for one step do not have to be imprinted from outside thesystem, but are established in the preceding step by themselves. Mentionmay be made by way of example here, for example, of temperature changesdue to exo- or endothermic reactions, changes in the pH due to reactionproducts from crosslinking reactions or transition from homogeneous toheterogeneous reaction, which can take place, for example, if a polymeror any polymer structure no longer dissolves due to crosslinkage, but ispresent suspended as a solid.

If the stepwise adjustment and attachment is carried out in the presenceof the template compound, it is in particular possible that after eachstep the template compound is removed from the resulting polymericstructure and in the next step the same or another template compound isagain added. In this respect, the template compound can be removed, forexample, as a solution by means of filtration, osmosis or dialysis orremoved from the solid support.

All embodiments which are described above for steps which are carriedout in the absence of the at least one template compound can obviouslyalso be employed in steps in which the at least one template compound ispresent if the presence of the at least one template compound allows thespecific embodiment.

In a preferred embodiment, a polymeric structure which is adaptable to anumber of template compounds which are different from one another iscreated by crosslinkage of a polymeric structure in one or more steps inthe absence of the at least one template compound. For example, this canbe carried out by producing by crosslinkage a polymeric structure whichhas two- and/or three-dimensional pores which are accessible to thesetemplate compounds and where the chemical structure of these pores isconstituted such that the template compounds can interact with thepores. Inter alia, it is possible here that all pores are similar,accessible to all different template compounds and are constituted suchthat the template compounds can interact with these pores. Obviously, itis also possible that two or more pores which are different from oneanother are formed, where each pore type can be accessible to at leastone of the desired template compounds. Likewise, it is possible thatsome of the pores are not accessible to the desired template compounds,but are made accessible after further adaptation, for example bycrosslinkage, as described above, to at least one of the desiredtemplate compounds.

In a further preferred embodiment of the process according to theinvention, at least one suitable support material is employed in thepreparation of the polymer network.

The term “suitable support material” here includes all support materialswhich can interact covalently or non-covalently with at least one of thepolymers employed and/or with at least one structure which results fromat least one step in which the adaptation according to (ii) and/orattachment according to (iii) takes place. Likewise, this term includesall support materials which can be crosslinked covalently ornon-covalently with at least one of the polymers employed and/or with atleast one structure which results from at least one step in which theadaptation according to (ii) and/or attachment according to (iii) takesplace, using at least one crosslinking reagent.

Accordingly, inter alia, support materials are possible which aresoluble in the at least one solvent in which the polymeric network isprepared or are present suspended as solid. Likewise, it is possiblethat in the case where a solvent exchange takes place or a solvent isadded during the preparation of the polymeric network the at least onesupport material which is firstly present suspended as a solid goes intosolution or is firstly present dissolved and then present suspended as asolid. If two or more different support materials are employed, thesecan obviously be present separately from one another in solution or besuspended as a solid.

In the case where the at least one support material is a solid, itssurface can essentially be of any desired shape. Inter alia, forexample, plane surfaces such as in the case, for example, of glass ormetal plates or curved surfaces or surfaces embedded in porous materialssuch as tubular or spongy surfaces such as in, for example, zeolites,silica gel or cellulose beads are possible.

In particular, the present invention includes embodiments of the processaccording to the invention in which the polymeric network is prepared onat least one of these suitable support materials.

The present invention accordingly also relates to a process, asdescribed above, characterized in that the polymeric network is preparedon at least one support material.

Inter alia, it is possible here that the polymeric network is preparedfirst and then applied to the at least one support material. Likewise,it is possible that the polymeric network is prepared in the presence ofthe at least one support material and the polymeric network is thenapplied by, for example, crosslinkage to this or another supportmaterial. If the preparation of the polymeric network, as describedabove, is carried out in two or more stages, it is possible to bring thepolymeric structure which results from any step into contact with the atleast one support material and, for example, to apply it thereto bycrosslinkage. If two or more different support materials are employed,it is possible to employ these together or alternatively separately fromone another. In the case of stepwise preparation of the polymericnetwork, it is possible, for example, after each step to add supportmaterial, where, if appropriate, different support material can beemployed in each case.

Accordingly, the process according to the invention also opens up thepossibility of influencing the conformation of the at least one polymer,which is adapted to at least one template compound in at least one step,via the at least one support material. In particular, the at least onesupport material can be a polymer or a polymer network, where a polymernetwork prepared according to the invention can also be employed as asupport material. Here, inter alia, a general copying process isaccessible which makes it possible, for example, to produce a number ofconsecutive positive and negative prints.

In a preferred embodiment, the polymeric network is prepared accordingto a process in which the at least one polymer is applied in layers toat least one support material.

The term “layer”, as is used in the context of the present application,here includes, inter alia, both layers in which the at least one polymeris applied in loose tangles and layers in which the at least one polymeris applied in largely untangled form.

In a first embodiment, the at least one polymer is applied in such a waythat it is in largely untangled structure, but is brought into contactwith support material and/or polymer layer already applied as closely aspossible above the theta point. In this embodiment, for the solution inwhich this at least one polymer is dissolved and brought into contactwith support material and/or polymer layer, a solvent or solvent mixtureis selected in which the polymer is present in largely untangled form,where obviously the untangled form of the polymer can be assisted by thespecific choice of other reaction conditions such as temperature,pressure or pH. Here, an optimization preferably takes place betweenpolymer folding and partition coefficients of the polymer which are aslarge as possible. For this preferred embodiment, polymers are veryparticularly preferably used which have a molar mass of less thanapproximately 30,000 g/mol. By means of this embodiment, the applicationof largely monomolecular polymer layers is favoured.

In a second embodiment, solvent or solvent mixture or other reactionconditions are selected in such a way that the at least one polymer isfound in the solution in the vicinity above the theta point. By means ofthis specific embodiment, which is very particularly preferably favouredby polymers having a molar mass in the range of more than approximately30,000 g/mol, it is possible to favour the application of the polymer inloose polymer tangles.

In a third embodiment, solvent or solvent mixture or other reactionconditions are chosen such that the at least one polymer is found in thesolution in the vicinity below the theta point. Here, inter alia, it ispossible to apply nanoparticles formed from the at least one polymer.

Application in layers is possible, inter alia, by bringing into contactat least one suitable support material with a suitable polymer and thepolymer being spontaneously arranged on the at least one supportmaterial in layers under the chosen reaction conditions, where at leastone conformation of the polymer can be adapted and fixed in the presenceor absence of the at least one template compound, as described above.Likewise, it is possible to employ two or more different suitablepolymers simultaneously, which are arranged on the support materialspontaneously in layers under the chosen reaction conditions. Here too,at least one conformation of at least one of the polymers can be adaptedand fixed in the presence or absence of the at least one templatecompound, as described above.

On application, in principle all polymers such as those alreadydescribed above can be employed. The molar mass of the polymers employedis preferably in the range from 2,000 to 100,000 g/mol, furtherpreferably in the range from 5,000 to 30,000 g/mol.

Preferably, the application of one or more polymers in layers is carriedout in individual steps.

Accordingly, the present invention also relates to a process, asdescribed above, which is characterized in that the at least one polymeris applied to the at least one support material in layers in at leasttwo successive steps.

As already described above, it is possible here, inter alia, to firstprepare a polymeric structure which consists of two or more layers,where this can be carried out in one or alternatively a number of steps.In one or more further steps, this polymer structure can then be appliedto the at least one support material, where, if appropriate, at leastone further layer can be applied to the polymeric structure in one ormore further steps. The adaptation of at least one conformation of atleast one of the polymers involved can be carried out according to oneor more of the embodiments already described above. Since it is possiblein the process according to the invention to prepare nanoparticles, itis possible, in particular, to apply nanoparticles to the supportmaterial which are present in dissolved, colloidally dissolved orsuspended form.

In a preferred embodiment, in a first step one or more layers of atleast one polymer are applied to at least one support material. In atleast one further step, at least one further layer is then applied tothe resulting structure. Each layer here can comprise identical polymersor alternatively two or more polymers which are different from oneanother. The adaptation of at least one conformation of at least one ofthe polymers involved can be carried out according to one or more of theembodiments already described above.

In a particularly preferred embodiment, the application of the at leastone polymer in layers to the at least one support material is carriedout according to a process in which a layer of a polymer is firstapplied covalently, preferably non-covalently, to at least one supportmaterial. In a further step, at least one crosslinking reagent is addedin the presence or absence of the at least one template compound in sucha way that the crosslinkers react via at least one functional group withthe polymer applied to the support material, so that preferably apredominant part of the crosslinking reagents is able, in each case viaat least one further functional group, to react with at least onefurther polymer which is applied in the next layer. In a next step, afurther layer of at least one further polymer is then applied andcrosslinked with the first polymer layer by reaction with the functionalgroups already mentioned. After this, one or more further steps canfollow, in which crosslinking reagent in each case reacts with a polymerlayer, at least one further polymer is added and a new polymer layer isformed via crosslinking with the polymer layer applied beforehand. Eachstep here can be carried out in the presence or absence of the at leastone template compound.

In the case of the preparation of the polymeric network in layers in thepresence or absence of the at least one template compound, it isnecessary under certain circumstances, in the case of the formation of anew layer, to avoid crosslinkages within at least one of the layersalready applied to the support material and/or between the polymerswhich are intended to form the new layer. In this connection, threeparticularly preferred embodiments (a) to (c) may be mentioned,according to which this application in layers can take place, which withrespect to (a) and (b) can further particularly preferably be used withnon-specific or non-selective crosslinking reagents:

(a) In a first process variant, the reaction of an already appliedpolymer layer takes place with the at least one crosslinking reagent atlow temperature, the crosslinking reagent predominantly reacting at oneend. The at least one, preferably dissolved, polymer for the next stepis then added, the reaction conditions being varied in a suitable mannersuch that a reaction takes place mainly with the polymer then added.

(b) In a second process variant, a polymer structure which comprises oneor more polymer layers applied to at least one support material, ismixed together with a polymer solution from which the second polymerlayer is to be formed, and at least one crosslinking reagent. By meansof a suitable modification of the reaction conditions, which can becarried out slowly or rapidly, conditions are established in which theat least one crosslinking reagent reacts simultaneously with the polymerlayer already present and the polymers which are intended to form thenext layer, with formation of this layer, the crosslinkage describedabove, which is to be avoided, being exceeded for entropy reasons by thepreferred crosslinkage, which leads to the formation of the new layer.

(c) In a third process variant, the reaction is carried out with twodifferent temperatures or pHs or solvents or solvent mixtures or otherdifferences in the reaction conditions using a specific or selectivecrosslinker.

In a very particularly preferred embodiment, the method (a) is carriedout such that the cross-linking reagent is brought into contact with thepolymer layer applied last at temperatures at which the crosslinkingreagent is statistically uniformly distributed over the polymer layeralready present and at which a reaction of the crosslinking reagent withthe polymer layer already present largely [lacuna]. The temperatures atwhich the reaction is carried out in this respect are as a rule in therange from 0 to −70° C.

In the choice of the other reaction conditions such as, for example, pH,nature of the solvent, concentration of the crosslinking reagent in thesolvent, in this preferred embodiment of the process care is also to betaken that the reaction of the crosslinking reagent with the polymerlayer present largely does not occur until the crosslinking reagent isstatistically uniformly distributed over the polymer layer alreadypresent.

By means of appropriate variation of the reaction conditions, in a nextstep the statistically uniformly distributed crosslinking reagent isreacted with the polymer layer already present in such a way that thecrosslinking reagent mainly reacts via one or more functional groups andat least one functional group of the crosslinking reagent, via which thecrosslinkage to the next polymer layer takes place, does not react withthe polymer layer already present. As a rule, this again takes place atlow temperatures, these as a rule being in the range from 0 to −10° C.This is further favoured by the use of short-chain crosslinking reagentsand/or the immobilization of the polymer layer. Possibilities as to howthis crosslinkage can be induced, inter alia, are, for example, alsoapplication of ultrasound or photochemical crosslinkage.

Obviously, it is also possible, in the case of appropriate crosslinkingreagents and/or in the case of an appropriate polymer layer alreadypresent, to control the reaction procedure described above by variationof the pH and/or variation of the solvents and/or by addition ofmodifiers, obviously combinations of one or all methods also beingpossible.

In this connection, reference can also be made to the specific methodswhich can be used as described above in order initially to suppress thebonding of a polymer and to stimulate it in a further step.

According to method (a), in a next step a solution which comprises theat least one polymer, which is to be applied as the next polymer layer,is brought into contact with the reaction product of crosslinkingreagent and polymer layer already present. The reaction conditions arethen modified such that the reaction particularly preferably takes placebetween the non-reacted functional groups of the crosslinking reagentbonded to the polymer layer already present and the polymers to beapplied as the next polymer layer. Inter alia, it is also possible herethat the reaction conditions are influenced by addition of the solutionwhich comprises the at least one polymer which is to be applied as thenext polymer layer in such a way that a further modification of thereaction conditions no longer has to take place.

With respect to this step of application of the next polymer layer,reference can also be made, inter alia, to the specific methods whichcan be used as described above in order first to suppress the bonding ofa polymer and to stimulate it in a further step.

In a likewise particularly preferred embodiment, the method according to(b) is carried out in such a way that the solution, comprising the atleast one crosslinking reagent and the at least one polymer, is broughtinto contact with the last-applied layer of the at least one polymerunder reaction conditions in which firstly no reaction takes place, butboth crosslinking reagent and polymer to be applied are statisticallyuniformly distributed over the polymer layer already present.

As already described in connection with the method (a), in a preferredembodiment this bringing into contact takes place at low temperatures,as a rule in the range from 0 to −70° C.

In the choice of the other reaction conditions such as, for example, pH,nature of the solvent, concentration of the crosslinking reagent in thesolvent or concentration of the polymer to be applied in the solvent, inthis preferred embodiment of the process care is also to be taken thatthe reaction of the crosslinking reagent with the polymer layer presentand the reaction of the polymer to be applied with the crosslinkingreagent largely does not occur and the crosslinking reagent and thepolymer to be applied are statistically uniformly distributed over thepolymer layer already present.

In a next step, the reaction conditions are then modified in such a waythat the crosslinking reagent reacts both with the polymer layer alreadypresent and with the polymer which is applied as the next layer. Here,it is possible, inter alia, that the crosslinking reagent reacts firstwith the polymer layer already present and then with the polymer to beapplied with formation of the new polymer layer. Likewise, it ispossible that the crosslinking reagent reacts simultaneously with thepolymer layer already present and the polymer to be applied withformation of the new polymer layer. It is further possible that thestatistically uniformly distributed crosslinking reagent reacts firstwith the statistically uniformly distributed polymer and the reactionproduct then reacts with the polymer layer already present withformation of the new polymer layer. If the reactions of the crosslinkingreagent with the polymer layer already present on the one hand and thepolymer to be applied on the other hand do not take placesimultaneously, it is possible, by variation of the reaction conditions,first to carry out one of the reactions, and by further variation of thereaction conditions to carry out the other reaction.

As far as the modification of the reaction conditions is concerned,reference may be made here to all possibilities and combinations alreadydescribed above. In particular, with respect to this step of theapplication of the next polymer layer, reference can also be made, interalia, to the specific methods which can be used as described above inorder first to suppress the bonding of a polymer and to stimulate it ina further step. Possibilities as to how this crosslinkage can beinduced, inter alia, are, for example, also use of ultrasound orphotochemical crosslinkage.

Use of ultrasound or photochemical crosslinkage are obviously methodswhich in principle can be employed very generally in any crosslinkingstep such as is carried out in the context of the present invention.

The term “selective/specific crosslinking reagent” is understood in thecontext of the present invention as meaning a crosslinking reagent whichhas two or more different functional groups, of which at least onegroup, in comparison with at least one group which is differenttherefrom, preferably reacts with a functional group of a furtherpolymer or the support material under given reaction conditions. Theterm furthermore includes those crosslinking reagents which have two ormore identical functional groups, but whose chemical environment differsand/or which are sterically differently arranged and of which thereforeat least one preferably reacts with a functional group of a furtherpolymer or the support material under given reaction conditions.Likewise, this term comprises those crosslinking reagents which havefunctional groups which are identical to or different from one another,which therefore differ in selectivity/specificity, because some of thefunctional groups are activated with an activating reagent according toa process such as described above. Obviously, in the compounds whichhave two or more different functional groups, one or alternatively anumber of the functional groups can be activated with reactive groupswhich are optionally different such that the reactivity of one part ofthe optionally activated groups differs from the reactivity of the otherpart of the optionally activated groups. Combinations of two or more ofthe described influences, which act on the specificity/selectivity, areobviously likewise possible.

In a particularly preferred embodiment, the application in layers iscarried out in the presence or, preferably, absence of the template suchthat a degree of crosslinking is present between the layers which leadsto an insoluble, but swellable polymer network which preferably hasinteraction cells which are capable of interaction with the at least onetemplate compound. In these interaction cells, in general, thefunctional groups of the swellable polymer network are on average in asteric arrangement which is favourable according to distance and anglewith respect to the interaction with the at least one template compound.

In a further preferred embodiment, the conformation of this swellablepolymer structure is adapted in the presence of the at least onetemplate compound to the at least one template compound in at least onelayer and fixed by crosslinkage.

The present invention therefore also relates to a process, as describedabove, characterized in that the application in layers leads to aswellable polymer network which has a conformation which is adapted tothe at least one template compound in at least one further step in thepresence of the at least one template compound and is fixed bycrosslinkage.

With respect to the application in layers to at least one supportmaterial, all suitable crosslinking reagents such as have already beendescribed above can be employed.

By way of example, bivalent epoxides, isocyanates, amidines,chlorotriazines or aldehydes may be mentioned. Those preferred are, forexample, succinimide derivatives, particularly preferably ONB- andN-hydroxyphthalimide-activated reagents. In a further preferredembodiment, bivalent, symmetrical or unsymmetrical crosslinking reagentsare employed. For example, activated dicarboxylic acids may be mentionedhere. In a further embodiment, specific or selective crosslinkers areemployed. These can be, for example, polybasic carboxylic acids,diamines, diols or further suitable compounds which are activated withdifferent reactive groups. Likewise, they can be compounds having atleast two functional groups which are different from one another, whichon activation with one compound or with two or more compounds which aredifferent from one another on activated groups which are different fromone another have different reactivity.

The chain length of the crosslinking reagents is essentially arbitraryand can be adapted to the particular requirements of the reactionprocedure and/or to the polymers employed and/or to the at least onetemplate compound. The chain length here can reach from 2, such asoxalate, up to chain lengths of oligomers or polymers. The chain of thecrosslinker itself can be aliphatic and/or araliphatic and/or aromaticand for its part can carry functional groups which, for example, havebeen introduced specifically into the chain, for example by a processfor the preparation of a polycondensation product, as described above,and which are suitable for interaction with the at least one templatecompound and/or for a further crosslinkage, as is the case, for example,with, inter alia, oligoethylene oxide.

In a very particularly preferred embodiment, the last crosslinking stepwhich takes place in the adaptation of the conformation of the polymericnetwork and the fixing of the preferred conformation of the polymericnetwork is carried out by a rigid crosslinking reagent such as, forexample, terephthalic acid or biphenylcarboxylic acid. Obviously, thiscrosslinkage by a rigid crosslinker can be carried out either withpolymeric networks prepared in solution or on a support.

For the preparation of the swellable polymer network, inter alia,crosslinking reagents with flexible chains having a chain length in therange from 4 to 24 atoms, particularly preferably from 8 to 12 atoms,are preferably employed.

On application of a layer of at least one polymer to the at least onesupport material, a solvent or solvent mixture is very particularlypreferably used in which the at least one polymer is largely present indenatured form, for example above the theta point. By means of this veryparticularly preferred embodiment, the deposition of a monomolecularlayer of the at least one polymer on the at least one support materialis favoured. In a likewise very particularly preferred embodiment, thisdeposition of monomolecular layers is furthermore promoted by thespecific use of polymers having molar masses of less than 30,000 g/mol.

Obviously, it is of course also possible to work in the vicinity of thetheta point, whereby, for example, the deposition of loose polymertangles on the at least one support material can be achieved. Withrespect to this embodiment, polymers are preferred whose molar mass isin the range from approximately 30,000 to approximately 100,000 g/mol.

In this respect, the deposition can also be promoted by addition of atleast one poor solvent and/or by modification of the pH and/or byaddition or buffers and/or salts and/or suitable organic auxiliaries. Itis likewise possible to concentrate the solution in which the at leastone polymer is present in dissolved or suspended form, where in aparticularly preferred embodiment the concentration of the at least onepolymer in the liquid phase is kept approximately constant. On accountof this, it is possible to apply the at least one polymer approximatelyquantitatively as a layer on the at least one support material.

As far as the deformation of the conformation of the at least onepolymer into a preferred conformation and the subsequent crosslinkage,this is preferably carried out in the process according to the inventionin all procedures outlined above in solution or on a support, veryparticularly preferably such that, in order to achieve the establishmentof the preferred conformation of the polymer in the presence of thetemplate compound, the reaction is carried out at high temperatures,preferably in the range from more than 50° C., particularly preferablyin the range from 60 to 105° C. and further particularly preferably inthe range from 70 to 80° C. Obviously, this temperature range can betailored to the solvent or solvent mixture employed. In a further step,the crosslinking reagent is added at low temperatures, preferably in therange from 0 to −70° C., whereby a statistically uniform distribution ofthe crosslinking reagent over the polymer is preferably achieved. Bysuitable variation of the reaction conditions, as already describedabove, following this the reaction of the polymer with the crosslinkingreagent is induced.

In a likewise preferred embodiment, the process is carried out withrespect to all procedures in such a way that on applying the polymer asolvent or solvent mixture is employed in which the polymer is close tothe insolubility limit, whereby the distribution coefficient for theapplication of the polymer assumes a favourable value. Particularlypreferably, the process is carried out such that the polymer is in thevicinity of the theta point. In this preferred manner of carrying outthe reaction, it is avoided, inter alia, that the polymer precipitates.

The at least one solvent is further preferably selected in such a waythat the interactions of the interaction cells, such as are described inthe context of the present invention, with the solvent are largelynegligible compared with the interactions of the interaction cells withthe template compound.

The deformation in the presence of the template compound is furtherpreferably performed in solvent mixtures of defined polarity dependingon the functional groups which [lacuna] on the crosslinker and/or in thepolymer strand and/or in the side chains of the polymer which, forexample, form the abovementioned interaction cells. In particular,organic and/or aqueous solvents are suitable here, the pH of thesolutions further preferably being in the range from 4 to 9 andparticularly preferably in the range from 6 to 8. As solvents which arepreferred, inter alia, mention may be made, for example, ofchlorohydrocarbons having up to 3 carbon atoms, such as chloroform, ornitrites, such as acetonitrile, or esters, such as ethyl acetate, orketones, such as methyl ethyl ketone or acetone, or open-chain or cyclicethers such as methyl tert-butyl ether or tetrahydrofuran or dioxane, oroptionally suitably substituted aromatics such as toluene or xylene, ormixtures of two or more thereof.

In a particularly preferred embodiment, the adaptation of theconformation of the polymer to a template compound is carried out inaccordance with the process according to the invention in a solventmixture and under reaction conditions in which the polymer is largelyinsoluble, but the template compound is soluble.

In an embodiment which is preferred, inter alia, all process steps,individually or in suitable combinations, can be carried out ascombinatorial test methods.

It is possible here, for example, to adapt the conformation of a polymeror of a polymeric structure which, for example, is preferably applied toa support, in a combinatorial test method to a number of differenttemplate compounds and to crosslink the resulting preferredconformations, identical polymers or polymeric structures in each casebeing brought into contact here with different template compounds ineach case.

Likewise, it is possible, for example, to react identical templatecompounds with a number of different polymers or polymeric networks ineach case and, for example, to crosslink the preferred conformationsobtained.

Obviously, it is also possible to carry out process steps in thepreparation of the polymeric network in combinatorial test methods,where it is possible, inter alia, to vary the support, the polymer, forexample with respect to the degree of derivatization and/or the numberand nature of the receptor groups, the crosslinking reagent, for examplewith respect to the chain length, the number and/or the nature of thefunctional groups, the degree of crosslinkage in the polymeric networkor alternatively the number of layers applied to the support.

Additionally preferably, these combinatorial test methods can be coupledwith statistical experimental planning. Such combinatorial orstatistical/combinatorial methods can accordingly also be used for thepreparation of the polymer derivatives as described above, crosslinkingreagents, for the preparation of a polymeric network on a support or insolution or alternatively for testing the polymeric network inapplication areas such as are described, for example, below.

Particularly suitable for these combinatorial orstatistical/combinatorial test methods are, inter alia, flow processes,variants such as automation by means of valve circuits, reagentrecycling or stop-flow techniques also being possible. These flowprocesses can be employed under suitable boundary conditions even forthe production of relatively large amounts of the polymer derivatives asdescribed above, crosslinking reagents and polymer networks on a supportor in solution.

In addition to the process for the preparation of the polymeric network,the present invention also relates to the polymeric network itself,which is preparable according to a process as described above.

In a likewise preferred embodiment, polymeric networks in the form ofclusters, microlatices and/or nanoparticles are obtained from theprocess according to the invention. These can be processed further as atrue solution, or as a colloidal solution or suspension. In particular,these clusters, microlatices and/or nanoparticles can be crosslinkedcovalently and/or non-covalently to layers, for example to membranes orsolids, which, for example, can be porous. This crosslinkage can in turnalso take place according to the process according to the invention, andthe resulting structure can be adapted to one or more template compoundsand fixed by means of this crosslinkage. By specific choice of thepreparation and of the procedure, for example by addition of, forexample, suitable pore formers, stabilizers, detergents, protectivecolloids, suitable solvent mixtures, by the manner of stirring,ultrasonic treatment or particle generation by spraying, it is possible,for example, to prepare preferably round particles having a specificporosity.

Inter alia, two methods for the preparation of the clusters,microlatices and/or nanoparticles are particularly preferred in thecontext of the process according to the invention.

In one method, a polymer of sufficient molar mass, preferably having amolar mass in the range from 30,000 to 100,000 g/mol, is introduced insuch a high dilution and/or under such further reaction conditions thatthe polymer is present largely in tangled form. In particular, thechoice of the solvent which assists this tangled form is important here.With addition of crosslinker, these polymer tangles, if appropriate inthe presence of template compound, are intramolecularly crosslinkedwithout intermolecular crosslinkage taking place. The functional groupslying on the outside of the polymer tangle are also reacted with thecrosslinking reagent here. By means of these outsides activated in sucha way, it is then possible in a further step to crosslink thenanoparticles intermolecularly, where depending on the chain length ofthe crosslinking reagents via which the crosslinkage takes place and/ordepending on the at least one template compound which is optionallypresent in the intermolecular crosslinkage, the mesh width of theresulting structure, such as a porous membrane, can be controlled.

In the other method, the process is carried out in such a way that thefunctional groups on the outside of the intramolecularly crosslinkedpolymer tangle are not reacted with crosslinker. In a further step, thesolution which comprises the polymer tangles is concentrated, whereby,with sufficient concentration, the polymer tangles agglomerate to givethree-dimensional structures by reaction of the functional groups lyingon the outside.

In contrast to the imprinting phases prepared according to the priorart, the polymer networks prepared according to the invention have, forexample, the advantage of a significantly higher loading ability. Theloading ability here indicates how many grams of a substrate arecontained per gram of the coated support material. Values between 4 and7% are typical here. With respect to the mass of the actually activepolymer layer, this loading ability is already in the order of magnitudeof preferably 30 to 50% with 3 layers. By the application of furtherpolymer layers, it is thus possible to increase the percentage loadingability of the coated support material again markedly.

While the imprinting phases have a loading ability which is customarilyin the per thousand range, it is possible without problems to preparepolymer networks by the process according to the invention which have aloading ability in the percent range. In the industrial application ofthe polymers prepared according to the invention, a significantly highereconomy can thus be achieved.

In principle, the polymeric networks prepared according to the inventioncan be employed in all suitable processes. Processes are particularlypreferred here in which the at least one preferred conformation which isfixed by crosslinking and which is adapted to at least one templatecompound is utilized. Accordingly, application areas which may bementioned are, for example, preferably substance separation processessuch as liquid-chromatographic or gas-chromatographic processes,membrane separation processes, dialysis processes, or substanceconversion processes such as homogeneous or heterogeneous catalysis.

The polymers prepared according to the invention can further be employed

-   -   as an assay or in a (rapid) test in combination with analytical        or diagnostic methods, courses and/or detection reagents,    -   as a support for substances which are to be released, for        example in a controlled manner, inter alia, under defined        conditions, where “drug release” should be mentioned as a        keyword here,    -   as a sensor, indicator or detector on surfaces or in cavities,        or    -   as a medicament or vaccine for, for example, competitive        inhibition or blocking of antigenic groups, for example of        receptors or epitopes on cells, cell constituents,        microorganisms, allergens, whereby, for example, passive        immunization can be achieved.

In a likewise preferred use, the polymeric network prepared according tothe invention is employed in substance preparation processes. Examplesof these which may be mentioned, inter alia, by way of example arereproduction processes. Here, using the polymers prepared according tothe invention, copies of largely arbitrary (macro)molecular patterns canbe prepared and these can in turn be copied, a duplicate of the originalpattern which is isosteric, for example, preferably with respect tonanoenvironment, resulting. In the context of the process according tothe invention, receptors of interest of a pattern can be scanned hereand this negative converted into a positive isosteric to the receptor.The present invention therefore also describes the use of the processaccording to the invention in substance preparation processes. In thecase where this embodiment is used in drug design, a novel,pharmacologically active substance can be bonded to the isostericpositive, for example, without side effects, tested or catalyticallysynthesized. The present invention thus also includes supralithographicreproduction techniques in the nano range, whose products can then inturn be employed, for example, for active immunizations.

Accordingly, the present invention also relates to the use of apolymeric network, preparable according to a process as described above,in substance separation processes, substance conversion processes,substance preparation processes, substance recognition processes or forthe detection of signals. With respect to signals which can be detected,optical, electrical or mechanical signals, inter alia, may be mentioned.

The present invention is illustrated in greater detail with the aid ofthe following examples.

EXAMPLE 1 Coating of silica gel SP 300-15/30 with poly(benzylN-allylcarbamate) of degree of derivatization 14% and subsequentcrosslinkage of the polymer with dodecanedioic acidbis(N-hydroxy-5-norbornene-2,3-dicarboximide) ester

Poly(benzyl-N-allylcarbamate) having a degree of derivatization of 14%(1.60 g) was dissolved in boiling glacial acetic acid (100 ml, about117° C.), diluted with dichloromethane (100 ml, 1.18 mol) after coolingand treated with pyridine (112 ml, 1.42 mol) in order to impair thesolubility of the polymer. Subsequently, the resulting turbidity waseliminated using a few drops of glacial acetic acid. After addition ofsilica gel 300 Å, 20 μm (Daisogel SP 300-15/30) (10.02 g), the mixturewas agitated on a shaker for 30 minutes and, after filtering off withsuction through a glass frit, washed with dichromomethane (4×50 ml).

For crosslinkage, the coated silica gel was added to a solution ofdodecanedioic acid bis(N-hydroxy-5-norbornene-2,3-dicarboximide) ester(46 mg, 83 μmol) and triethylamine (36 mg, 0.35 mmol) in dichloromethane(60 ml) and the suspension was concentrated to dryness in vacuo (85mbar, water bath 0° C.). The coated silica gel was washed withtetrahydrofuran (60° C., 4×25 ml), filtered off with suction andsubsequently washed with dichloromethane (50 ml).

For the second coating, poly(benzyl N-allylcarbamate) having a degree ofderivatization of 14% (1.60 g) was dissolved in boiling glacial aceticacid (100 ml, about 117° C.), diluted with dichloromethane (100 ml, 1.18mol) after cooling and treated with 100 ml of pyridine (100 ml, 1.26mol) in order to impair the solubility of the polymer.Dimethylaminopyridine (DMAP, 80 mg, 0.65 mmol) and further pyridine (12ml, 0.15 mol) were then added. Subsequently, the resulting turbidity waseliminated using a few drops of glacial acetic acid. After addition ofthe silica gel which was reacted and coated with the crosslinker, asdescribed above, the mixture was agitated on a shaker for 30 minutesand, after filtering off with suction through a glass frit, washed withdichloromethane (4×50 ml).

The coated silica gel was again crosslinked as described above and thencoated with a third polymer layer, according to the second method.

The mixture was swollen in dimethylformamide in a frit (30 min). Byslowly passing through a solution of diethylamine (2 ml, 1.42 g, 19.41mmol) in DMF (40 ml), the residual activated crosslinker groups weredeactivated. For complete deactivation, the mixture was rinsed a furtherfour times with the filtrate solution. The mixture was then washed withtetrahydrofuran (60° C., HPLC grade, 4×50 ml) and with dichloromethane(4×50 ml) and sucked dry.

The coated silica gel was treated with glacial acetic acid (100 ml), thesuspension was heated to boiling, and the solid was filtered off withsuction, washed with dichloromethane (5×50 ml), dried (110° C., 16 h)and sieved through a 45 μm sieve.

The final weight was 9.4 g.

EXAMPLE 2 Polymer Deformation and Subsequent Crosslinkage

Explanation of the Compounds:

-   -   Silica gel 300 Å, 20 μm (Daisogel SP 300-15/30), coated with 3        layers of poly(benzyl N-allylcarbamate) having a degree of        derivatization of 7%, which are crosslinked to 2% with        dodecanedioic acid bis(N-hydroxy-5-norbornene-2,3-dicarboximide)        ester=(1),    -   succinic acid bis(N-hydroxy-5-norbornene-2,3-dicarboximide)        ester=(2)

A column packed with (1) was conditioned with 0.2% strength (10.5mmol/l) 5-methyl-5-phenylhydantoin solution (substrate) in CHCl₃ and aflow of 0.6 ml/min, about 40 mg of the substrate being adsorbed on thecolumn. 80 μl of glacial acetic acid were then injected and the outflowwas collected in two fractions:

1st fraction: From the injection up to the reattainment of the baselineafter the substrate peak (6.1 min).

-   -   18.2 mg of the substrate were contained in this fraction. Of        this, the amount of substrate rinsed in by the eluent in this        time of 7.32 mg was subtracted so that a value of 10.9 mg        resulted for the amount rinsed out by the glacial acetic acid.        2nd fraction: From the reattainment of the baseline after the        substrate peak up to the fresh adjustment of the equilibrium        present before injection (6.1 to 80 min).    -   72.2 mg of substrate were found in this fraction. As 88.7 mg had        been rinsed in by means of the eluent in this time (73.9 min),        the amount of substrate taken up from the stationary phase was        16.5 mg.

After completion of the injection, the column was dismantled and cooledto 0° C. (about 30 min).

For the preparation of a crosslinker solution, (2) (186.2 mg, 0.423mmol) was dissolved in 19.24 ml of 0.2% strength (10.5 mmol/l)5-methyl-5-phenylhydantoin solution and triethylamine (0.76 ml) wasadded. This solution was rinsed into the system (without column) from astorage vessel cooled to 0° C.

After the baseline was constant, the column was again incorporated intothe system so that here it furthermore remained cooled to 0° C. Thecrosslinker solution was rinsed into the column at 5 ml/min. After thebreakthrough of the crosslinker front (UV 265 nm), the flow was stopped.

The column was again dismantled, furthermore cooled to 0° C. for 30 minand then laid in a column thermostat (120 min, 25° C.).

The system (without column) was rinsed with tetrahydrofuran, and thecolumn was incorporated into the system again after a reaction time of120 min and rinsed with 50 ml of tetrahydrofuran (1 ml/min).

For the deactivation of the still remaining freeN-oxy-5-norbornene-2,3-dicarboximide groups of the crosslinker,diethylamine (40.2 mg, 0.55 mmol) (5 equivalents based on maximumN-hydroxy-5-norbornene-2,3-dicarboximide formed) was dissolved (quenchsolution) in tetrahydrofuran (20 ml), rinsed into the column (1 ml/min),the solution from the column outflow was rinsed into the column againfor 5 h and then switched to tetrahydrofuran. After the baseline becameconstant, the pump was stopped, the column thermostat was set to 50° C.and this temperature was maintained for 30 min. The tetrahydrofuran wasthen additionally pumped at 1 ml/min until pure tetrahydrofuran waseluted.

1. A process comprising, in the following order: (i) crosslinking apolymer; (ii) reversibly binding the polymer to a template that isdissolved or suspended in a solvent, whereby the polymer acquires aconformation adapted to the template, the template being a chemicalcompound or a biological structure; (iii) removing the template from thepolymer; and (iv) exposing the polymer to the template wherein thetemplate is attracted to and adheres to the polymer.
 2. The process ofclaim 1, wherein step (ii) further comprises fixing the conformationobtained by further crosslinking.
 3. The process of claim 1 wherein step(ii) includes two reaction steps having reaction conditions differentfrom each other.
 4. The process of claim 3 wherein, after each of thetwo steps, the conformation obtained from the respective step is fixedby crosslinking.
 5. The process of claim 4 wherein at least one of thetwo crosslinking steps is carried out in the absence of the template. 6.The process of claim 1 wherein the interaction enthalpy between thepolymer and the template in step (iv) is increased by more than 0.1kcal/mol as compared to the enthalpy between the polymer and thetemplate in step (ii).
 7. The process of claim 1 wherein step (iv)includes exposing the polymer to a mixture of the template and othersubstances for separating the template from the other substances.
 8. Theprocess of claim 1 wherein step (iv) concurrently enhances a conversionof the template.
 9. The process of claim 1 wherein step (iv)concurrently enhances detecting the presence of the template by thepolymer.
 10. The process of claim 1 wherein step (iv) concurrentlyenhances an output of a signal in response to the presence of thetemplate adhered to the polymer.
 11. The process of claim 1 whereinafter performing step (ii) with a first template, step (ii) is repeatedwith a different template to adapt the cross-linked polymer to bothtemplates.
 12. A process comprising, in the following order: (i)reversibly binding a polymer to a template that is dissolved orsuspended in a solvent, whereby the polymer acquires a conformationadapted to the template, the template being a chemical compound or abiological structure; (ii) fixing the conformation obtained from step(i) by crosslinking the polymer; (iii) removing the template from thepolymer; and (iv) exposing the polymer to the template wherein thetemplate is attracted to and adheres to the polymer.
 13. The process ofclaim 12 wherein step (ii) includes two reaction steps having reactionconditions different from each other.
 14. The process of claim 13wherein, after each of the two steps, the conformation obtained from therespective step is fixed by crosslinking.
 15. The process of claim 14wherein at least one of the two crosslinking steps is carried out in theabsence of the template.
 16. The process of claim 12 wherein step (iv)includes exposing the polymer to a mixture of the template and othersubstances for separating the template from the other substances. 17.The process of claim 12 wherein step (iv) concurrently enhances aconversion of the template.
 18. The process of claim 12 wherein step(iv) concurrently enhances detecting the presence of the template by thepolymer.
 19. The process of claim 12 wherein step (iv) concurrentlyenhances the output of a signal in response to the presence of thetemplate adhered to the polymer.